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1
Stöckle, Silke. "Thin liquid films with nanoparticles and rod-like ions as models for nanofluidics." Phd thesis, Universität Potsdam, 2010. http://opus.kobv.de/ubp/volltexte/2010/4637/.
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With the rise of nanotechnology in the last decade, nanofluidics has been established as a research field and gained increased interest in science and industry. Natural aqueous nanofluidic systems are very complex, there is often a predominance of liquid interfaces or the fluid contains charged or differently shaped colloids. The effects, promoted by these additives, are far from being completely understood and interesting questions arise with regards to the confinement of such complex fluidic systems.
A systematic study of nanofluidic processes requires designing suitable experimental model nano – channels with required characteristics. The present work employed thin liquid films (TLFs) as experimental models. They have proven to be useful experimental tools because of their simple geometry, reproducible preparation, and controllable liquid interfaces. The thickness of the channels can be adjusted easily by the concentration of electrolyte in the film forming solution. This way, channel dimensions from 5 – 100 nm are possible, a high flexibility for an experimental system. TLFs have liquid IFs of different charge and properties and they offer the possibility to confine differently shaped ions and molecules to very small spaces, or to subject them to controlled forces. This makes the foam films a unique “device” available to obtain information about fluidic systems in nanometer dimensions.
The main goal of this thesis was to study nanofluidic processes using TLFs as models, or tools, and to subtract information about natural systems plus deepen the understanding on physical chemical conditions. The presented work showed that foam films can be used as experimental models to understand the behavior of liquids in nano – sized confinement.
In the first part of the thesis, we studied the process of thinning of thin liquid films stabilized with the non – ionic surfactant n – dodecyl – β – maltoside (β – C₁₂G₂) with primary interest in interfacial diffusion processes during the thinning process dependent on surfactant concentration 64. The surfactant concentration in the film forming solutions was varied at constant electrolyte (NaCl) concentration. The velocity of thinning was analyzed combining previously developed theoretical approaches. Qualitative information about the mobility of the surfactant molecules at the film surfaces was obtained. We found that above a certain limiting surfactant concentration the film surfaces were completely immobile and they behaved as non – deformable, which decelerated the thinning process. This follows the predictions for Reynolds flow of liquid between two non – deformable disks.
In the second part of the thesis, we designed a TLF nanofluidic system containing rod – like multivalent ions and compared this system to films containing monovalent ions. We presented first results which recognized for the first time the existence of an additional attractive force in the foam films based on the electrostatic interaction between rod – like ions and oppositely charged surfaces. We may speculate that this is an ion bridging component of the disjoining pressure. The results show that for films prepared in presence of spermidine the transformation of the thicker CF to the thinnest NBF is more probable as films prepared with NaCl at similar conditions of electrostatic interaction. This effect is not a result of specific adsorption of any of the ions at the fluid surfaces and it does not lead to any changes in the equilibrium properties of the CF and NBF. Our hypothesis was proven using the trivalent ion Y3+ which does not show ion bridging. The experimental results are compared to theoretical predictions and a quantitative agreement on the system’s energy gain for the change from CF to NBF could be obtained.
In the third part of the work, the behavior of nanoparticles in confinement was investigated with respect to their impact on the fluid flow velocity. The particles altered the flow velocity by an unexpected high amount, so that the resulting changes in the dynamic viscosity could not be explained by a realistic change of the fluid viscosity. Only aggregation, flocculation and plug formation can explain the experimental results. The particle systems in the presented thesis had a great impact on the film interfaces due to the stabilizer molecules present in the bulk solution.
Finally, the location of the particles with respect to their lateral and vertical arrangement in the film was studied with advanced reflectivity and scattering methods. Neutron Reflectometry studies were performed to investigate the location of nanoparticles in the TLF perpendicular to the IF. For the first time, we study TLFs using grazing incidence small angle X – ray scattering (GISAXS), which is a technique sensitive to the lateral arrangement of particles in confined volumes. This work provides preliminary data on a lateral ordering of particles in the film.Mit dem Heranwachsen der Nanotechnologie in den vergangenen zehn Jahren hat sich die Nanofluidik als Forschungsbereich etabliert und erfährt wachsende Aufmerksamkeit in der Wissenschaft, sowie auch in der Industrie. Im biomedizinischen Bereich, wo intrazelluläre Prozesse häufig komplexer, nanofluidischer Natur sind, wird sich vermehrt für ein detailliertes Verständnis von nanofluidischen Prozessen interessiert, z.B. für den Einfluss von Kolloiden verschiedenster Form oder elektrischer Ladung auf die Kanäle und auf das Fließverhalten oder die Auswirkungen der Einengung von Flüssigkeiten und Kolloiden in Nanometer Geometrien. In der vorliegenden Arbeit werden dünne flüssige Filme, hinsichtlich ihrer Funktion als nanofluidische Modelle untersucht. Im ersten Teil der Arbeit wurde die Fließgeschwindigkeit des Fluids aus dem dünnen Film, abhängig von der Konzentration der filmstabilisierenden Tensidmoleküle n – Dodecyl β – D – Maltoside ( β – C₁₂G₂) bei einer konstanten Elektrolytkonzentration von 0.2 mM NaCl untersucht. Mit einem theoretischen Modell konnte das Dünnungsverhalten nachgezeichnet werden. Es wurde eine kritische Tensidkonzentration gefunden, unter der die Oberflächen lateral mobil sind und über der sie sich wie fest verhalten. Dadurch konnten wir Aufschluss darüber erlangen, wie die Oberfläche des Films unter verschiedenen Bedingungen geschaffen ist, und das in Bezug zur Verteilungsdichte der Moleküle an den Oberflächen setzen. Im weiteren wurden komplexere, nanofluidische Systeme untersucht, wobei zum einen ~ 1 nm lange, stäbchenförmige, multivalent geladene Spermidin - Moleküle die punktförmigen Elektrolyte ersetzten. Es konnte eine deutliche Veränderung der Stabilität zwischen Filmen mit und ohne Stäbchen festgestellt werden. Die Filme, mit NaCl, blieben länger in dem metastabilen „Common Film“ (CF) Zustand als die Filme, die eine vergleichbare Konzentration von Spermidin Stäbchen beinhalteten. Die Ergebnisse deuteten auf eine zusätzliche Anziehungskraft durch Brückenbildung zwischen zwei geladenen Oberflächen durch gegensätzlich geladene Stäbchenförmige Moleküle hin. Es konnte gezeigt werden, dass dieser Effekt weder ein Ergebnis von spezifischer Ionenadsorption an die Filmoberfläche war, noch ein Unterschied in den Gleichgewichtszuständen von den Dicken der CFs und der Newton Black Films (NBFs) hervorrief, was auf die korrekte Annahme der Ionenstärke in der Lösung schließen ließ. Auch in Versuchen mit ebenfalls trivalenten Ionen YCl3 wurde festgestellt, dass kein vergleichbarer Überbrückungseffekt auftritt. Die Ergebnisse wurden mit theoretischen Simulationen verglichen und es wurde eine quantitative Übereinstimmung gefunden bezüglich der Größe des Systeminternen Energiegewinns durch den Überbrückungseffekt. Desweiteren wurde das Fließverhalten von Fluiden mit Kolloiden eingeengt in Nanometer Geometrien untersucht. Für zwei verschiedene Arten von Nanopartikeln (Fe3O4 stabilisiert mit Oleinsäure und polymerstabilisierte Goldpartikel) wurde eine Verlangsamung der Fließgeschwindigkeit festgestellt. Mit einem theoretischen Modell konnte das Fließverhalten nur für enorm erhöhte Viskositätswerte des Fluids erklärt werden. Die Viskositätserhöhung wurde mit Partikelaggregaten, die den Ausfluss behindern, erklärt und diskutiert, unter der Annahme eines nicht - Newtonischen Fließverhaltens der Dispersionen. Gleichermaßen wurde die strukturelle Anordnung der Partikel in den Filmen hinsichtlich ihrer vertikalen und lateralen Verteilung untersucht. In dieser Arbeit werden vorläufige Ergebnisse präsentiert, die noch weiteren Studien bedürfen. Mit Neutronenreflexion sollte die Anordnung der Partikel orthogonal zur Oberfläche im Film analysiert werden. Eine qualitative Analyse lässt schließen, dass bei einer höheren Konzentration von Partikeln in Lösung, sich auch eine erhöhte Konzentration von Partikeln im dünnen Film befindet. Leider konnten die Daten nicht hinsichtlich der Lage der Partikel analysiert werden. Zum ersten Mal wurden dünne flüssige Filme mit Kleinwinkelröntgenstreuung unter streifendem Einfall (GISAXS) analysiert. Mit Hilfe dieser Methode sollte eine laterale Anordnung der Partikel im Film untersucht werden. Es konnten erfolgreiche Messungen durchgeführt werden und mit Hilfe der rechnergestützten Analyse konnte eine Aussage gemacht werden, dass ~ 6 nm große Teilchen in ~ 43 nm Abstand sich im Film befinden. Die Aussage bezüglich der kleinen Teilchen könnte sich auf einzelne, kleinere Partikel beziehen, allerdings könnten auch die 43 nm eine relevante Strukturgröße darstellen, da es in der Dispersion gehäuft Aggregate mit dem Durchmesser in dem Größenbereich vorliegen. Zusammenfassend können sich mit dieser Arbeit die dünnen flüssigen Filme als eine wichtige Kernmethode der Untersuchung von nanofluidischen Prozessen, wie sie häufig in der Natur vorkommen, behaupten.
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Almeida, Maria de Lurdes Soares de. "Selective protection of polyamines : Synthesis of spermidine derivatives." Doctoral thesis, Universidade do Porto. Reitoria, 1989. http://hdl.handle.net/10216/10192.
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Almeida, Maria de Lurdes Soares de. "Selective protection of polyamines : Synthesis of spermidine derivatives." Tese, Universidade do Porto. Reitoria, 1989. http://hdl.handle.net/10216/10192.
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Nadaraia-Hoke, Shorena Flanagan John M. "Structural and thermodynamic characterization of spermidine and spermine synthases." [University Park, Pa.] : Pennsylvania State University, 2009. http://etda.libraries.psu.edu/theses/approved/PSUonlyIndex/ETD-4555/index.html.
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Choucair, Bassima. "Synthèse des polyaminostérols, analogues de la squalamine, à propriétés antibiotique et anticancéreuse." Caen, 2003. http://www.theses.fr/2003CAEN3098.
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La squalamine est un polyaminostérol 3 -N-[3N-(4-aminobutyl)aminopropyl] aminocholestan-7 -ol-24R-sulfate qui a été isolé en 1993 de tissus du requin " Squalus acantias ". Cette molécule a montrée des propriétés antibiotique et anticancéreuse par inhibition de l'angiogénèse dans les tumeurs solides. Cependant, la squalamine est présente en quantités infimes dans les tissus du requin et sa synthèse nécessite plusieurs étapes. D'où l'intérêt de synthétiser des analogues désulfatés de la squalamine. Le polyamine a été introduit en position C-7 du cholestérol, en positions C-7 et C-6 du cholestanol. Ces analogues sont les premiers exemples où la position de la spermidine a été modifiée. Les analogues synthétisés de la squalamine montrent un large spectre d'activité antimicrobienne. Ils présentent également une cytotoxicité vis-à-vis des cellules cancéreuses NSCLC-N6 (CI 50 < 3. 3 g/ml). La squalamine devient le chef de file d'une nouvelle famille d'antibiotiques et d'anticancéreux.
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Catros, Véronique. "Implication des polyamines dans les processus proliferatifs malins." Rennes 1, 1990. http://www.theses.fr/1990REN1T085.
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Des etudes effectuees in vivo chez l'animal ainsi que chez des patients atteints de differents types histologiques de tumeurs, ont permis de montrer que le taux erythrocytaire de spermidine (spd) se comportait comme un index sanguin de la proliferation cellulaire tumorale. L'etude in vivo du metabolisme des polyamines (pa) apres administration de precurseurs radiomarques a des animaux porteurs de tumeurs greffees a permis d'apporter la preuve de l'origine tumorale de la spermidine erythrocytaire. Les modalites d'uptake des pa par les erythrocytes ont par ailleurs ete caracterisees in vitro: les erythrocytes de souris cancereuses presentent des modifications de leurs proteines stromales, leur conferant la capacite de capter trois fois plus de #1#4c spd que les erythrocytes de souris saines. A l'inverse de ce qui se passe au cours d'un processus proliferatif controle, ou l'evolution des taux erythrocytaires de pa est parfaitement regulee, en cas de cancer, les pa s'accumulent dans les hematies. Cette accumulation est correlee a une reduction de la concentration tissulaire en malonaldehyde (mda), une molecule inhibitrice de la replication de l'adn. L'etude du catabolisme des pa dans les cellules cancereuses ainsi que l'utilisation de drogues modulatrices de ce metabolisme permettent d'evoquer l'hypothese d'un role des pa erythrocytaires dans le controle homeostatique de la proliferation cellulaire. Les effets biologiques obtenus avec des analogues tetramethyles de pa permettent egalement d'envisager l'utilisation du metabolisme des pa a des fins therapeutiques et diagnostiques en cancerologie
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Sanvura, Bashwira. "Myricoïdine et dihydromyricoïdine, nouveaux alcaloïdes macrocycliques dérivés de la spermidine." Doctoral thesis, Universite Libre de Bruxelles, 1990. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/213135.
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Suttmann, Rebecca T. "Purification and inhibition of spermidine N⁸-acetyltransferase from rat liver nuclei." Scholarly Commons, 1991. https://scholarlycommons.pacific.edu/uop_etds/2222.
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The naturally occurring polyamines play an essential role in cell growth and proliferation. The enzyme spermidine N8- acetyltransferase catalyzes the acetylation of spermidine utilizing acetyl-CoA as the acetyl donor. In this study, an in vitro acetyltransferase assay was used to determine the types of compounds which can inhibit this reaction. The enzyme was partially purified from rat liver nuclei and solubilized in 0.4 M KCl. The Km for spermidine was 0.47 mM. Studies on the nature of the active site indicated that: (i) a sulfhydryl group is essential for optimal activity as shown by inhibition with parahydroxymercuribenzoate and N -ethylmaleimide, (ii) a metal ion does not appear to be necessary for catalytic activity of this enzyme since EDTA, 2,2-dipryridil, and 1,10 phenanthroline were poor inhibitors of this enzyme, (iii) a lysine or another primary amine is likely to play a crucial role in this reaction since succinate anhydride and 2,4,6-trinitrobenzene sulfonic acid were effective inhibitors of this reaction and (iv) tyrosine is not likely present at the catalytic site since N -acetylimidazole produced no inhibition.
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Caron, Édith. "Étude de l'interaction entre l'actine et les polyamines : spermidine et spermine." Thèse, Université du Québec à Trois-Rivières, 1987. http://depot-e.uqtr.ca/5803/1/000560724.pdf.
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Garcie, Christophe. "Modulation atypique de la biosynthèse de la colibactine, une génotoxine de Escherichia coli, ou comment un îlot génomique est en symbiose avec le chromosome bactérien." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30283/document.
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L'îlot génomique pks code une machinerie de biosynthèse complexe synthétisant la colibactine, une génotoxine produite par certaines souches de Escherichia coli. Cette génotoxine induit des cassures double-brin de l'ADN sur les cellules eucaryotes in vitro et in vivo. La colibactine n'est pas une protéine, mais un métabolite secondaire de type polycétide/peptide non-ribosomal (PK/NRP). Des résultats préliminaires de l'équipe semblaient indiquer que certains gènes du core genome de E. coli seraient également impliqués dans la production de la colibactine. L'objectif de cette thèse était d'identifier les gènes non-essentiels de E. coli situés hors de l'îlot génomique pks impliqués dans la synthèse de colibactine, en construisant une banque de mutants par insertion de transposons. Ce criblage a permis d'identifier 29 gènes candidats, mais deux groupes de gènes ont été particulièrement étudiés dans la suite du projet : trois gènes codants des protéines chaperons, et trois gènes codant des enzymes impliquées dans le métabolisme des polyamines. Le premier projet a permis de montrer que la protéine chaperon HtpG (ou Hsp90Ec), homologue bactérien de la protéine de choc thermique eucaryote Hsp90, est requise pour la production de colibactine, mais aussi de yersiniabactine, un sidérophore (ou système bactérien de captation du fer) appartenant à la même famille chimique que la colibactine. De plus, la protéase ClpQ intervient de concert avec Hsp90Ec dans la production de colibactine et de yersiniabactine. Ces résultats confirment ainsi l'interconnexion entre la synthèse des deux facteurs de virulence de E. coli, la colibactine et la yersiniabactine. Enfin, l'analyse des effets de la mutation du gène htpG au cours d'une infection systémique chez l'animal, dans des modèles de sepsis et de méningite néonatale chez les rongeurs, démontre le rôle de la protéine de réponse au stress Hsp90Ec dans la virulence de E. coli. Le second projet a révélé que les polyamines sont impliquées dans la production de colibactine. L'étude du métabolisme des polyamines par une approche de microbiologie moléculaire a démontré que la spermidine est la polyamine nécessaire à la production de colibactine. Les résultats préliminaires de ce projet indiquent que la spermidine participerait à la régulation de l'expression de certains gènes de l'îlot génomique pks, et de fait modulerait la biosynthèse de colibactine. Des études complémentaires sont en cours pour élucider les mécanismes impliqués. Les résultats de cette thèse sont une illustration parfaite de l'intégration symbiotique d'un élément génétique mobile acquis au cours de l'évolution au sein du chromosome bactérien, grâce à plusieurs connexions bilatérales permettant la production de facteurs de virulence par E. coliThe pks genomic island codes a complex biosynthetic assembly line that synthetizes the colibactin, a genotoxin produced by some strains of Escherichia coli. This genotoxin generates DNA double-strand breaks in eukaryotic cells both in vitro and in vivo. Colibactin is not a protein, but a secondary metabolite belonging to the chemical family of hybrid polyketide/nonribosomal peptide compounds. Preliminary results from our research team suggested that certain genes of the E. coli core genome (i.e. genes present in all strains of the species) could also be involved in the colibactin production. The main goal of this thesis was to identify non-essential E. coli genes located outside the pks island that are required for colibactin biosynthesis, with the screening of a transposon mutant library. This revealed 29 potential candidate genes, but the project focused specifically on two groups of genes: three genes encoding chaperone proteins, and three genes encoding enzymes involved in polyamines metabolism. The first project highlighted the role of the molecular chaperone HtpG (or Hsp90Ec), the bacterial homolog of eukaryotic heat shock protein 90, in the production of colibactin, but also yersiniabactin, a siderophore (i.e. a bacterial iron uptake system) that belongs to the same chemical family as colibactin. Furthermore, the ClpQ protease was involved in colibactin and yersiniabactin production in combination with Hsp90Ec. These results confirmed the interplay between the biosynthesis of two E. coli virulence factors, colibactin and yersiniabactin. Finally, analysis of the effects of htpG disruption during systemic infection in animals, using rodent models of sepsis and neonatal meningitis, demonstrated the role of the stress-responsive molecular chaperone Hsp90Ec in E. coli virulence. The second project revealed the involvement of polyamines in the biosynthesis of colibactin. A molecular microbiology approach demonstrated that spermidine was the polyamine required for colibactin production. Preliminary results suggested that spermidine could regulate the expression of some pks island genes, and therefore could modulate colibactin production. Further experiments are in progress to elucidate the molecular mechanisms involved in this regulation. Together, the results of this thesis perfectly illustrate the symbiotic integration of a mobile genetic element acquired during evolution into the bacterial chromosome, through several crosstalks allowing the production of virulence factors in E. coli
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Kammula, Rao Karunakara. "Purification, characterization and inhibitor studies of rat liver nuclear spermidine N-acetyltransferase." Scholarly Commons, 1994. https://scholarlycommons.pacific.edu/uop_etds/2783.
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Polyamines are ubiquitously present in all living cells. The abnormal metabolism of polyamines that is associated with certain types of cancers has been the focus of several investigations. Enzymes that are involved in the transacetylation of polyamines have been studied extensively, so as to develop inhibitors of these enzymes which may be used as drugs in cancer therapy. Based on indirect evidence, the nuclear spermidine acetyltransferase has been thought to be a critical enzyme that is associated with genetic derepression leading to cancerous growth. In the present study a novel, rapid, sensitive and highly reproducible radio chemical procedure has been developed for assaying spermidine (polyamine) acetylation. The study contains data showing range of linearity of the procedure, percent product recovery, as well as low interference from the unreacted acetyl coenzyme A. Rat liver nuclear spermidine acetyltransferase has been purified using the biochemical procedures annmonium sulfate precipitation, DEAE chromatography, Hydroxyapatite chromatography, Diaminobutyl agarose chromatography and Polyacrylamide P-300 gel filtration. The enzyme obtained at the end of such procedures was found to be essentially homogeneous as seen on native gel electrophoresis. The purified enzyme has been shown to have an isoelectric point of 5.2. Bicine and Hepes were found to be more suitable as buffering species for good enzyme activity. The enzymatic reaction velocity was found to increase with temperature upto 36$\sp\circ$C and was found to increase linearly up to four minutes under non limiting conditions in the presence of 20% glycerol. Using the purified enzyme it has also been established that of the three nuclear polyamines, spermidine is the preferred substrate. The apparent Km for acetyl Co A with spermidine as substrate was found to be about 5 mM. The purified enzyme does acetylate histones. All the substrate analogs containing aminobutylamino group are acetylated by the enzyme.
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Li, Jun. "A study of the role of spermidine/spermine N¹-acetyltransferase (SSAT) in polyamine homeostasis in human prostate cancer cells." Thesis, University of Aberdeen, 2014. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=210088.
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Prostate cancer is the second leading cancer in men. A large amount of polyamines are synthesised in the human prostate and are involved in prostate cell growth and its physiological functions. The content of intracellular polyamines is closely related to cell growth. An increase in cell growth is accompanied by a rise of intracellular polyamine content, and a depletion of intracellular polyamine pools can cause growth arrest or cell death. Therefore, maintaining polyamine concentrations is critical to the cell. Spermidine/spermine N1-acetyltransferase (SSAT) is the first and rate-limiting enzyme in the polyamine catabolic pathway. SSAT gene is highly inducible, with many stimuli including polyamine analogues and some anticancer drugs producing dramatic increases in activity. Many studies have focussed on polyamine analogues as inducers of SSAT activity as increases in SSAT are associated with a growth inhibition in many tumour cells. However, the mechanisms of this inhibition are not fully understood with respect to polyamine content. Additionally, in vivo results in SSAT transgenic mice studies are contradictory. For example, prostate carcinogenesis is reduced in TRAMP mice but Apcmin/+ mice show a promoted intestinal tumorigenesis. It is thus necessary to characterise the regulation of polyamine content and metabolism by SSAT in prostate cancer cells. The aim of the present study was to characterise the role of SSAT in both the growth of LNCaP prostate carcinoma cells and the response of these cells to anticancer drugs. Our hypothesis is that increased SSAT activity will inhibit cell growth and that this is associated with a decrease of intracellular polyamine pools. Furthermore, if SSAT induction is an essential part of the response of cancer cells to anticancer drugs, then altered SSAT activity should affect sensitivity of the cells to the drugs. The present study used a cell culture model of human prostate cancer: LNCaP wild type (WT) and SSAT cDNA transfected prostate carcinoma cell lines. The expression of SSAT in the transfected cell line (SSAT- & SSAT+) was controlled through the “Tet-off” system. This model system provided a background for comparison of effects under basal (WT), low (SSAT-), and high (SSAT+) SSAT activity. Due to our interest in acetylpolyamine derivatives and their low concentrations in cells, a new method for quantifying polyamine concentrations was developed using liquid chromatography-mass spectrometry (LC-MS). This method was highly sensitive and can detect polyamines about 250 fold lower than HPLC, as well as N-acetylpolyamines and N1,N12-diacetylspermine. In addition, a variety of methods were utilised to measure cell growth, enzyme activity, protein expression, polyamine efflux and apoptosis, which includes enzyme assays, western blot, radiochemical labelled assays, flow cytometry, spectrophotometry and fluorescent microscopy. A stable increase in SSAT activity was inhibitory to the cell growth. This inhibition was associated with significant changes in the activity of the polyamine pathway. The alterations included an increase in ODC, APAO, and SMO activity; an accumulation of intracellular N1-acetylspermidine and putrescine; a decrease in intracellular spermidine and spermine; an increased polyamine flux and efflux; and an increase in apoptosis. Combination treatment to the cells with DFMO and MDL72527 partially restored the growth of SSAT+ cells. The original contribution of this study to the field is that the cells with a higher SSAT activity are less sensitive to aspirin and 5-FU, and the sensitivity increased while the overexpressed SSAT activity decreased. The growth inhibition was associated with a depletion of total intracellular polyamine pools by the drug treatments. Moreover, to our knowledge, it is first time that the extracellular polyamine concentrations were quantified by LC-MS in human tumour cells. Overall, an increase in SSAT activity led to an inhibition of prostate cancer cell growth, and vice versa. Thereby, this study suggests that SSAT is a potential target for novel drug discovery for cancer chemotherapy or chemoprevention. For example, a combination treatment could be designed that acts as an inducer of SSAT activity in tumour cells, leading to an inhibition of the cell growth in the first place and increased sensitivity to cytotoxic agents. This would then be followed by an agent to decrease SSAT activity when the sensitivity of cancer cells to the cytotoxic treatment was optimal.
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Warren, John C. III. "Evaluation of the Role of gsp, ygiC, and yjfC Genes in Glutathione Metabolism in Escherichia coli by Gene Disruption." Youngstown State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1310473424.
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Mackintosh, Caroline Anne. "Studies on the inhibition of plant pathogenic fungi by cyclohexylamine and spermidine analogues." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388547.
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Babbar, Naveen. "Regulation and function of spermidine/spermine N¹ acetyl transferase (SSAT) in colon carcinogenesis." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/289966.
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Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) have anti-tumorigenic activities against colorectal cancer. NSAIDs work by inhibiting cyclooxygenases (COX) enzyme. Sulindac, a NSAID prodrug, is metabolized into pharmacologically active sulfide and sulfone derivatives. Microarray analysis was used to detect COX independent effects of sulindac on gene expression in human colorectal cells. Spermidine/spermine N 1-acetyl transferase (SSAT) gene, which encodes a polyamine catabolic enzyme, was one of the genes induced by clinically relevant sulindac sulfone concentrations. Promoter analysis and mutational studies were done to map the sulindac sulfone dependent response sequences in SSAT 5' flanking sequences, which led to the identification of two Peroxisome Proliferator Activated Receptors (PPARs) response elements (PPREs) in the SSAT gene. PPRE-2 is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPARgamma in the Caco-2 cells, while PPRE-1 is not required for the induction of SSAT by sulindac sulfone, but can be bound by both PPARdelta and PPARgamma. Clinically relevant concentrations of sulfone reduced intracellular polyamine levels, inhibited cell growth and induced apoptosis in colon cancer cells. Further, only sulindac sulfone induced apoptosis could be partially rescued by exogenous polyamines. Upon evaluating other NSAIDs for their action on SSAT gene expression, it was found that they induce SSAT mRNA in either a COX dependent or independent mechanism in colon cancer cells. Studies with physiologically relevant concentrations of aspirin show that these concentrations can induce SSAT expression thereby leading to a decrease in polyamine levels. Activating mutations in K-ras, which is a late process in colon carcinogenesis, led to the suppression of SSAT expression in the Caco-2 cells due to the inhibition of PPARgamma by ERK. K-ras didn't have any effect on the induction of SSAT by sulindac sulfone but partially abolished the apoptosis caused by sulindac sulfone, indicating a possible role of mutant K-ras in sulindac resistant colon polyps. Sulindac sulfone, or Exisulin(TM) have been recently used in clinical trials for the prevention of colon, lung and prostate cancer. The data shown here, suggest that one of the mechanisms, by which sulindac sulfone could act as a chemopreventive agent is to induce the expression of SSAT thereby leading to a decrease in the intracellular polyamines. This reduction in polyamines plays an important part in the apoptosis induced by sulindac sulfone in the colon cancer cells. Further, induction of SSAT seems to a general mechanism for different NSAIDs like aspirin, indomethacin, ibuprofen, sulindac and celecoxib in colon cancer. Aspirin is able to induce SSAT and decrease intracellular polyamines at physiological concentrations, which can lead to a significant reduction in adenoma recurrence. Also, activated K- ras suppressed SSAT, but was not able to abolish the induction of SSAT by sulindac sulfone indicating the potential of using sulindac sulfone in colon cancer chemoprevention.
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Chen, Alina. "New polyamine analogues as potential antineoplastic agents." Scholarly Commons, 2000. https://scholarlycommons.pacific.edu/uop_etds/2680.
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The naturally occurring polyamines play an essential role in cell growth and proliferation. The levels of polyamines have been shown to increase in rapidly proliferating cancer cells. Therefore, compounds that inhibit enzymes in polyamine biosynthetic pathway may have therapeutic potential. Compounds capable of providing both in vitro and in vivo inhibition of almost all enzymes in the polyamine biosynthetic pathway are known. An exception is the lack of an agent that inhibits spermidine/spermine N 1 -acetyltransferase (SSAT), the rate-limiting enzyme in the catabolism of polyamines. The design, synthesis and characterization of five new polyamine analogues as potential inhibitors of SSAT are presented. Three compounds, N 1 -[3-(propenamido) propyl]-1,4-diaminobutane dihydrochloride 5 , N 1 -[3-(maleimido)propyl]-1,4-diamino-butane dihydrochloride 7 and N 1 -[3-(2-bromoacetamido)propyl]-1,4-diaminobutane dihydrochloride 9 , were designed as active-site-directed affinity label inhibitors. Two compounds, N-[N-(5-acetamido-2-hydroxypentyl-3-aminopropyl)]-1,4-diaminobutane trihydrochloride 12 and N-[3-(2-hydroxyethylamino)propyl]-1,4-diaminobutane trihydrochloride 14 , were designed as transition state-like analogue inhibitors. These compounds were synthesized using one key intermediate, N-(3-aminopropyl)-N,N ′ -bis-(tert-butoxycarbonyl)-1,4-diaminobutane 3 . Three of these synthesized compounds, 5 , 7 and 12 were evaluated for their ability to inhibit SSAT. The enzyme used was a crude extract of human large cell undifferentiated lung carcinoma cell line NCI H157 cells. These synthetic analogues when tested against the crude enzyme extract at concentrations of 0.05, 0.1, 1 and 5 μM appeared to show no effects on the activity of SSAT.
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Chakrabarti, Nilanjana. "Functional Analysis and Characterization of Transporter of Putrescine and Spermidine (TOPAS1) in Phytophthora parasitica." Bowling Green State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu149874256456224.
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Gingras, Yves. "L'effet inhibiteur des polyamines spermine et spermidine sur le complexe protéique du photosystème II /." Thèse, Trois-Rivières, Université du Québec à Trois-Rivières, 1998. http://www.uqtr.ca/biblio/notice/tablemat/03-2195690TM.html.
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Mémoire (M.Sc.) - Université du Québec à Trois-Rivières, 1998.La table des matières est disponible en format électronique sur le site Web de la bibliothèque. CaQTU Bibliographie : f. [147]-158.
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Gingras, Yves. "L'effet inhibiteur des polyamines spermine et spermidine sur le complexe protéique du photosystème II." Thèse, Université du Québec à Trois-Rivières, 1998. http://depot-e.uqtr.ca/3546/1/000654648.pdf.
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Finokaliotou, Sophia. "Synthetic and biological studies of antiparasitic natural product derivatives." Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518105.
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Trypanosomiasis and Leishmaniasis are tropical diseases caused by the parasites Trypanosoma and Leishmania, that cause severe medical and economical problems for millions of people in the developing world. Trypanosomiasis can be divided into African and American trypanosomiasis, which are caused by Trypanosoma brucei and Trypanosoma cruzi respectively. There are more than 20 different species of Leishmania worldwide that cause Leishmaniasis, but the most severe infection, visceral leishmaniasis, is caused by Leishmania donovani. Both diseases are transmitted by blood sucking insects like the tsetse fly and the sand fly. The majority of existing drugs for trypanosomiasis and leishmaniasis are either too toxic or have low efficacy, and in some cases parasites have also developed resistance. There is therefore a pressing need to develop new chemotherapeutic agents, and in this context, the enzyme trypanothione reductase (TryR) has emerged as an attractive validated target for drug design. The natural product cadabicine, extracted from the plant Cadaba farinosa, is a diphenyl ether-containing macrocyclic spermidine alkaloid which has been identified as a potential inhibitor of TryR by virtual screening. In order to investigate the potential of cadabicine as a TryR inhibitor, an efficient synthetic route to the natural product was delivered. This work was focused on the preparation and combination of three key synthetic units, namely an orthogonally protected spermidine derivative and two functionalised cinnamic acid units. This approach lead to the formation of the macrocycle by an intramolecular nucleophilic aromatic substitution followed by a convenient conversion to the natural product. In the same manner cyclic and noncyclic analogues of cadabicine were prepared, in order to examine the structure-activity relationship of these alkaloids to TryR.
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Huang, Tien Liang. "Design, synthesis, and biological evaluation of inhibitors for N⁸-acetyspermidine deacetglase and spermidine N⁸-acetytransferase." Scholarly Commons, 1989. https://scholarlycommons.pacific.edu/uop_etds/2179.
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Previous studies active-site-directed metal coordinating reagents and substrate analogues of (N8-AcSpd) have indicated that the catalytic mechanism of N8-AcSpd deacetylase involved a transition state metal. Several ω-amino substituted carboxylic acids were tested and results confirmed the probability of the deacetylase having a mechanism similar to the metalloproteases. Based on these results, several analogues of spermidine containing metal coordinating ligands were designed and synthesized. In addition, a potential transition state analogue of the nuclear enzyme, spermidine N8-acetyltransferase (N8-SAT) was also synthesized. All compounds were assayed in a 100,000g cytosol fraction form rat liver for their ability to inhibit the acetylation of radiolabeled substrate, [acetyl-3H]-N8-AcSpd. The apparent Ki (app Ki) values were determined from Dixon plots. The apparent Km of N8-AcSpd for the cytosolic deacetylase is 11.0 μM.
Based on the results of this investigation and results obtained earlier in this laboratory, hypothetical models for the binding interactions of substrates and inhibitors to the active sites of N8-AcSpd deacetylase and N8-SAT are drawn schematically. The mechanism of catalysis of N8-AcSpd deacetylase also is proposed.
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Harkat, Mahboubi. "Etude moléculaire de la dilatation des récepteurs P2X." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ023.
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Les récepteurs P2X sont des canaux cationiques non sélectifs, perméables aux ions Na+, K+ et Ca2+. Leur activation par l’ATP, pour des potentiels de membrane proches du potentiel de repos des cellules, induit un influx de cations entraînant une dépolarisation membranaire. Les récepteurs P2X, issus de l’oligomérisation de trois sous-unités identiques (homotrimères) ou hétérologues (hétérotrimères), possèdent tous une partie hydrophobe transmembranaire et une partie hydrophile et glycosylée extracellulaire. Les récepteurs P2X sont impliqués dans de nombreux rôles physiologiques, et possèdent une grande distribution tissulaire. De plus depuis une vingtaine d’année un état de conductance particulier du canal a été découvert permettant le passage de grosses molécules. Nommé état dilaté ou dilatation du pore, cette état conductance était considéré comme un processus lent dissocier de l’état de conductance permanentant le passage des du Na+. Notre approche multiple nous a permis de comprendre le mécanisme de dilatation. Or suite à nos résultats en électrophysiologie, nous avons montré que les récepteurs étaient immédiatement dilatés dans une échelle de temps de la milliseconde. Les résultats obtenus avec nos molécules photoisomérisables ont permis de confirmer que la dilation était un processus rapide. Mais surtout de résoudre le mécanisme moléculaire de l’état dilaté. En effet sous l’effet de la lumière, deux mouvements ont pu être observés. Nous avons déterminé qu’une polyamine, la spermidine, pouvait passer à travers le canal, ce qui n’avait jamais été démontré auparavant. Nous pensons que ces résultats ouvrent de nouvelles perspectives physiologiques dans la signalisation P2XP2X receptors are nonselective cation channels, permeable to Na +, K + and Ca2 + ions. Their activation by ATP, for membrane potentials close to the resting potential of the cells, induces an influx of cations leading to membrane depolarization. P2X receptors, derived from the oligomerization of three identical (homotrimeric) or heterologous (heterotrimeric) subunits, all possess a transmembrane hydrophobic domain and an extracellular hydrophilic and glycosylated domain. P2X receptors involved in many physiological roles, and have a high tissue distribution. Moreover, since twenty years, a particular conductance of the canal has been discovered allowing the passage of large molecules; which named “dilated state or dilatation of the pore”, this conductance state was considered as a slow process dissociating from the state of conductance which allows the passage of Na+. Our several approach allowed us to understand the mechanism of dilation. However, following our results in electrophysiology, we showed that receptors were immediately dilated in a millisecond time scale. Our results with our photoisomerizable molecules confirmed that dilation was a rapid process. But above all, it solves the molecular mechanism of the dilated state. Indeed under the effect of light, two movements could be observed. We determined that a polyamine, spermidine, could pass through the canal, which had never been demonstrated before. We believe that these results open new physiological perspectives in P2X signaling
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Peters-Weigel, Sandra M. "Regulation of the speC gene encoding ornithine decarboxylase in Escherichia coli by putrescine, spermidine and cAMP." Thesis, This resource online, 1993. http://scholar.lib.vt.edu/theses/available/etd-08182009-040534/.
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Deeb, Faten. "The role of spermidine in the regulation of development and differentiation in spermatids of Marsilea Vesitita." College Park, Md.: University of Maryland, 2009. http://hdl.handle.net/1903/9185.
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Thesis (Ph.D.) -- University of Maryland, College Park, 2009.Thesis research directed by: Dept. of Cell Biology and Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Pietrocola, Federico. "Regulation of Autophagy by Acetyl Coenzime A : From the Mechanisms to a Revised Definition of Caloric Restriction Mimetics." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T039/document.
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L’autophagie est un processus d’autodigestion dans lequel la cellule dégrade ses propres composants dans le but de maintenir l’homéostasie dans ses conditions basales. En absence de nutriments, l’autophagie est activée et favorise la survie cellulaire en fournissant des substrats énergétiques résistant aux conditions de stress. Autophagie et métabolisme communiquent à différents niveaux; une baisse en métabolites richement énergétiques, tels qu’en ATP et en NADH, est détectée par des senseurs cellulaires (AMPK et SIRT1 respectivement) et mène à l’activation de l’autophagie. Ici, nous définissons un niveau supplémentaire de régulation de l’autophagie induite par le jeûne. Dans ce travail, nous montrons que cette privation en nutriments est caractérisée par une diminution rapide de l’Acétyl CoA, intégrateur majeur de l’état nutritionnel au carrefour du catabolisme des graisses, des sucres et des protéines. La baisse en AcCoA s’accompagne de la réduction proportionnelle des niveaux généraux d’acétylation des protéines ainsi que par l’induction de l’autophagie. Les manipulations destinées à augmenter ou diminuer les niveaux cytosoliques d’AcCoA, ciblant soit la synthèse mitochondriale soit son transport dans le cytoplasme, résultent en la suppression ou l’induction de l’autophagie aussi bien dans les cultures cellulaires que dans les tissus de souris. La déplétion en AcCoA impacte directement l’activité des KATs utilisant l’AcCoA comme substrat pour l’acétylation protéique. Nous avont montré que cette baisse en AcCoA réduit spécifiquement l’activité de EP300; cette KAT est en effet nécessaire à la suppression de l’autophagie à des niveaux élevés d’AcCoA, se comportant ainsi comme le senseur des niveaux cytosoliques d’AcCoA. A son tour, EP300 contrôle l’autophagie en inhibant les protéines autophagiques clés. Dans l’ensemble, nos résultats illustrent les fonctions de l’AcCoA cytosolique comme régulateur métabolique central de l’autophagie, délimitant ainsi des stratégies pharmacologiques centrées sur l’AcCoA qui permettent la manipulation thérapeutique de l’autophagie. En effet, la privation en nutriments et la restriction calorique sont connues pour jouer un rôle positif sur la santé et la longévité en promouvant leurs effets. Néanmoins, les stratégies basées sur la restriction calorique sont difficilement applicables en clinique. Ici, nous proposons une nouvelle définition biochimique des Mimétiques de la Restriction Calorique, composés imitant l’effet positif du jeûne. Dans notre contexte, un MRC est un composé capable de réduire l’acétylation protéique par des mécanismes distincts mais convergents: premièrement, par diminution des niveaux d’AcCoA, deuxièmement par inhibition directe des KATs, et enfin, par activation des protéines déacétylases. Ces résultats de l’exécution d’un programme cellulaire conduisent finalement à des effets pro-santé liés à la restriction calorique incluant mais non limités à l’autophagieAutophagy is a self-digestion process in which cell degrades its own components in order to maintain homeostasis in basal conditions. In absence of nutrients, autophagy is activated and promotes cell survival by providing energetic substrates to sustain stressful condition. Autophagy and metabolism crosstalk at different levels; a drop in energy-rich metabolites, such as ATP and NADH, is detected by cellular sensors (AMPK and SIRT1 respectively) and leads to autophagy activation. Here, we define a further regulatory level of starvation-induced autophagy. In this work, we show that nutrient deprivation is characterized by a rapid depletion of Acetyl CoA, a major integrator of the nutritional status at the crossroads of fat, sugar, and protein catabolism.Decrease in AcCoA is accompanied by the commensurate reduction in overall protein acetylation levels as well as by autophagy induction. Manipulations designed to increase or reduce cytosolic levels of AcCoA, either targeting mitochondrial synthesis or its transport in the cytoplasm, resulted in the suppression or induction of autophagy both in cultured cells and in mice tissues. Depletion of AcCoA directly impacts on the activity of cellular KATs, which use AcCoA as substrate for acetylating proteins. We showed that a drop in AcCoA specifically reduces the activity of EP300; this KAT was indeed required for the suppression of autophagy by high AcCoA levels, thus behaving as the sensor of cytosolic AcCoA levels. In turn, EP300 controls autophagy by inhibiting key autophagic proteins. Altogether, our results indicate that cytosolic AcCoA functions as a central metabolic regulator of autophagy, thus delineating AcCoA-centered pharmacological strategies that allow for the therapeutic manipulation of autophagy. Indeed, nutrient deprivation and caloric restriction are known to play pro-healthy and longevity promoting effects. Nonetheless, CR-based strategies are hardly suitable in clinical settings. Here, we propose a new biochemical definition of Caloric Restriction Mimetics, compounds that mimic the positive effects of nutrient starvation. In our setting, a CRM is a compound able to reduce protein acetylation through distinct but convergent mechanisms: first, by decreasing AcCoA levels, second by directly inhibiting KATs, third by the activation of protein deacetylases. This results in the execution of a cellular program ultimately leading to CR-related pro-healthy effects, including but not limited to autophagy
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Bakkali, Abdelhak. "Contribution à la synthèse de la myricoidine et de la dihydromyricoidine alcaloïdes macrocycliques dérivés de la spermidine." Doctoral thesis, Universite Libre de Bruxelles, 1997. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212238.
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Sindi, Kaïs. "Imidates : synthèse de sidérophores pouvant être modifiés par des antibiotiques : étude de leurs propriétés physico-chimiques." Paris 7, 2008. http://www.theses.fr/2008PA077112.
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Une méthode de synthèse d'imidazolides 3a-c, de benzimidazolides 4a-d, et de dérivés 2-substitués d'imidazo-[4,5b]-pyridine 4e-h par condensation de 1,2-diamines 2 sur des imidates N-acylés 1 est décrite et illustrée par une dizaine d'exemples (Chap. I). Dans le chapitre II, la synthèse de conjugués sidérophore-antibiotique est envisagée selon deux stratégies à partir d'une aminé secondaire 13 dérivée de la spermidine 5 et de l'acide 2,3-dihydroxybenzoïque 7. Deux stratégies de synthèse ont été développées. La première consiste à modifier l'aminé secondaire 13 par un espaceur en C3 ou C5 présentant une fonction de type carboxylique et conduit à quatre ligands 57-60. Dans la seconde, les espaceurs sont introduits sur l'antibiotique 29 sans qu'aucune protection fonctionnelle ne soit nécessaire. Si les conjugués sidérophore-antibiotique correspondants n'ont pu être obtenus jusqu'ici, une étude des propriétés acido-basiques des quatre ligands bis- catécholiques possédant une fonction aminé tertiaire, LEt3H₅, LEt5H₅, LAc3H₅, et LAc5H₅ (57-60), et celle de leurs ferrâtes montre que ces ligands se comportent comme des sidérophores. Dans la plupart des cas, l'attribution de tous les pKa a pu être effectuée pour chaque ligand, tandis que dans le cas des ferrâtes correspondants seuls les pKa moyens des protons catécholiques, en position ortho- et meta-, sont accessibles, ainsi que ceux des acides carboxyliques et des aminés. Enfin, une estimation des constantes d'affinité, b, et des pFes est proposée. Les valeurs obtenues sont comparables à celles de sidérophores to-catécholiques naturels, tel le composé de Tait II: The synthesis of imidazolides 3a-c, benzimidazolides 4a-d and imidazo-[4,5b]-pyridines 4e-h, starting from 7V-acyl imidates 1 and 1,2-diamines 2 is described. (Chap. I)In the second part, two synthesis strategies, SEA and AES, are developed in the aim of producing antibiotic-siderophore-like conjugates. A secondary amine 13 is first prepared from spermidine 5 and 2,3-dihydroxybenzoic acid 7. In the first strategy, a C3 or C5 linker, bearing a carboxylic moiety, is grafted onto the central nitrogen atom of the amine 13. After deprotection of the catechol groups, four ligands are obtained 57-60. In the second strategy, C3 and C5 linkers are directly grafted onto the unprotected antibiotic, ampicillin 29. Even if up-today the corresponding antibiotic-siderophore-like conjugates are not obtained, the studies of their acid-base properties and of their iron(III) chelates demonstrate these molécules, LEt3H₅, LEt5H₅, LAc3H₅, et LAc5H₅ (57-60), to behave as siderophores. Practically, ail the individual pKa values have been measured for the free ligands, while for their iron(III) chelates, only the average pKa values of both ortho- and meta- catecholic protons were obtained, and the carboxylic and amine ones. Then, their affinities for Iron(III), b, and their pFes deduced from kinetic experiments show these new bis-catecholic siderophores, LEt3H₅, LEt5H₅, LAc3H₅, et LAc5H₅, can compete with natural bis-catecholic ones, such as Tait’s compound II
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Seguineau, Menanteau Corinne. "Caracterisation et approche synthetique de macrocycles spermidiniques isoles d'une celastraceae neo-caledonienne : pleurostylia apposita (wallich) alston." Angers, 1995. http://www.theses.fr/1995ANGE0501.
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Bergeron, Christophe. "Les polyamines : agents diagnostiques et cibles thérapeutiques en oncologie pédiatrique." Rennes 1, 1993. http://www.theses.fr/1993REN1B006.
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Bertin, Aurélie. "Compréhension des mécanismes électrostatiques impliqués dans la plasticité structurale de la chromatine eucaryote." Paris 11, 2006. http://www.theses.fr/2006PA114813.
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Nous avons montré que les queues d'histones H3 et H4 sont nécessaires pour que des interactions attractives s'établissent entre NCPs, en présence d'ions monovalents. Pour cela, nous avons comparé des NCPs recombinantes intactes et gH3gH4 (sans queues H3 et H4) par SAXS. Les données expérimentales ont été comparées à des simulations établies à partir d'un modèle simple de potentiel d'interaction de paires. Les interactions entre NCPs gH3gH4 sont décrites par un potentiel de type répulsif uniquement. Par contre, l'introduction d'une composante attractive dans le potentiel est indispensable pour mieux décrire les données expérimentales obtenues avec des NCPs intactes aux concentrations salines les plus élevées. Par ailleurs nous avons montré que les NCPs gH3gH4 présentent une conformation légèrement moins compacte que celle de NCPs intactes. Nous avons mis au point des conditions d'imagerie optimales par cryomicroscopie électronique dans le but d'analyser finement ces différences conformationnelles par reconstruction d'image à trois dimensions. Afin de mimer les conditions d'encombrement et de compaction de la chromatine dans la cellule, nous avons concentré artificiellement des solutions de NCPs par ajout de cations multivalents ou par stress osmotique. L'effet des ions multivalents dans les interactions entre NCPs a été examiné. Plus particulièrement, nous avons étudié le rôle des ions magnésium2+ et spermidine3+ dans la précipitation des NCPs. Des diagrammes de phase on été établi afin de déterminer précisément les conditions de précipitation des NCPs en présence de Mg2+ et Spd3+. Ces diagrammes ont été comparés entre eux et confrontés aux diagrammes théoriques. L'organisation des NCPs au sein des domaines biphasique a été examiné par diffraction des rayons X, microscopies optique et électronique. Nous avons montré que la structure des phases denses obtenues dépend des conditions de précipitation.
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Ariyaratne, Menaka M. "A new perspective on polyamine biosynthesis and transport in arabidopsis thaliana." Bowling Green State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1555693507751475.
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Vargas, Ashley Joy. "Assessing the Role of Dietary Polyamines on the Continuum of Colorectal Carcinoma." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/293416.
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Putrescine, spermidine and spermine are the polyamines biosynthesized by human cells via ornithine decarboxylase (ODC) and are also sourced from the diet. Polyamines are required for malignant and normal cell growth and development. Pharmacological suppression of polyamine biosynthesis, by difluoromethylornithine, and inflammation, via sulindac, has demonstrated ~70% efficacy in preventing premalignant colorectal adenomas (CRA) in a clinical trial; however, high polyamine intakes mitigated this preventative action. Further, dietary polyamines increase the dysplasia of CRA in initiated animal models of colorectal cancer (CRC) and are hypothesized to function as tumor promoters. Human research on dietary polyamines was limited until the development of a dietary database in 2007 but, continues to be limited by the lack of a biomarker of exposure. Chapter 1 of this dissertation tests the hypothesis that dietary polyamines increase risk of CRA in polyp-formers (n = 1164) and found evidence to support this hypothesis. However, only women, younger participants and certain genotypes experienced more risk of CRA with high polyamine exposure. Chapter II tests the hypothesis that dietary polyamines increase the risk for CRC in an average risk cohort of post-menopausal women (n = 87,620) and did not find evidence to support this hypothesis in the whole population. Rather, dietary polyamines were non-significantly protective against CRC and significantly protective when paired with aspirin use and against CRC-specific death. There was some evidence to support an increase in risk of CRC in younger participants with high polyamine exposure. Overall, the first two chapters suggest that dietary polyamines protect the colorectum in normal risk individuals but promote carcinogenesis in high risk individuals. Chapter III tests the hypothesis that dietary polyamine intake correlates with urinary polyamine output in a group of overweight/obese, older men (n = 36) and Chapter IV tests the hypothesis that intake of highly ripe sweet cherries will increase urinary polyamine output in a subgroup of 10 men from Chapter III. The findings from these chapters suggest there may be a positive correlation, but that a better measure of dietary polyamine intake is needed to determine if urinary polyamines are biomarkers of exposure to polyamines.
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Searles, Lynne E. (Lynne Elizabeth). "Effects of orally administered spermidine on absorptive enzyme and nutrient transporter gene expression in the rat small intestine during postnatal development." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23298.
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The developmental profiles of mRNA and protein expression for ornithine decarboxylase (ODC), the Na$ sp+$-dependent glucose co-transporter (SGLT1), sucrase isomaltase (SI), and the Na$ rm sp+K sp+$ ATPase $ alpha sb1$ and $ beta sb1$ subunit isoforms in the postnatal rat small intestine, as well as the effects of exogenous spermidine on their precocious development, were examined. Postnatal age had a significant effect with all enzymes and the nutrient transporter maturing around weaning. Consecutive exposure to exogenous spermidine during suckling precociously induced ODC mRNA, SI protein, and SGLT1 gene expression in the proximal and distal small intestine. Levels of Na$ rm sp+K sp+$ ATPase $ alpha sb1$ and $ beta sb1$ subunit isoform mRNA were precociously induced in the proximal small intestine only. These findings show that exposure to exogenous spermidine can promote precocious alterations in intestinal enzyme and nutrient transporter expression; however, it appears that spermidine must be continuously supplied for these alterations to persist in suckling rats.
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Bauer, Julia [Verfasser], and Florian [Akademischer Betreuer] Lang. "Der suizidale Zelltod humaner Erythrozyten - Stimulation durch Sphingosin und Auswirkungen der biogenen Polyamine Spermin und Spermidin / Julia Bauer ; Betreuer: Florian Lang." Tübingen : Universitätsbibliothek Tübingen, 2013. http://d-nb.info/1160754489/34.
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Zhang, Hanlin. "Translational control of autophagy rejuvenates immune responses." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:9950cef9-7592-41b4-973c-c906edad23c8.
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As our body's guardian, the immune system maintains systemic health through removal of pathogens, damage and cancer. Ageing of the immune system is associated with compromised immune responses as well as decreased tumour surveillance and is therefore a key risk factor for major diseases in the elderly. Adaptive immune responses are mediated by T and B lymphocytes, and failure in adaptive immunity is a particular hallmark of the ageing organism. Here we show that autophagy is impaired in aged murine B lymphocytes, and loss of autophagy causes severely reduced B cell responses. Our data demonstrate that B cell senescence can be reversed in an autophagy-dependent manner by spermidine, a naturally occurring polyamine metabolite. Mechanistically, our study reveals that the translation factor eIF5A, that requires spermidine for its activation, regulates the expression of the master autophagy/lysosomal transcription factor TFEB. Importantly, we show in humans that spermidine, eIF5A and TFEB levels decrease with age and may serve as ageing biomarkers. Taken together our results indicate that the translational control of autophagy by eIF5A is dysregulated with ageing, and identify a novel pathway with therapeutic implications.
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Fredericks, Eugene B. (Eugene Bernard). ""Studies involving alterations of polyamine metabolism in Arabidopsis thaliana"." Monash University, Dept. of Biological Sciences, 2001. http://arrow.monash.edu.au/hdl/1959.1/8432.
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Vaishali, Mulangi Gopala Reddy. "Characterization of Polyamine Transporters from Rice and Arabidopsis." Bowling Green State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1303231265.
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Rioux, Benjamin. "Synthèse et vectorisation de biomolécules type Chalcone en vue d'une application anticancéreuse." Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0104/document.
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La synthèse et la vectorisation d’agents anticancéreux constituent des axes de recherche majeurs du LCSN. De nombreux composés naturels possèdent des propriétés anticancéreuses, mais ils sont abandonnés en raison de leur manque de sélectivité vis-à-vis des cellules cancéreuses ou de leur faible biodisponibilité. Ainsi, un grand intérêt est actuellement porté sur le développement de médicaments spécifiquement vectorisés vers les cellules cancéreuses. Les vecteurs utilisés dans ce travail sont des dérivés de polyamines et des nano objets de type β-cyclodextrines / nanocristaux de cellulose (β-CD/CNCx). Les polyamines vont permettre un ciblage actif des cellules cancéreuses grâce au système de transport de polyamine (PTS) surexprimé dans ces cellules. Les nano objets vont cibler spécifiquement les tumeurs via un ciblage passif dû à l’effet EPR. Les principes actifs employés dans cette étude sont des flavonoïdes, et plus particulièrement des chalcones. En effet, les flavonoïdes, qui constituent une large famille de composés phénoliques naturels, sont connus pour leurs nombreux effets biologiques comme les activités antioxydantes, anti-inflammatoires et anti-prolifératives.L’intérêt du LCSN à la fois pour les chalcones et les agents anticancéreux nous a conduits à concevoir de nouveaux composés antiprolifératifs vectorisés. Ce travail présente dans un premier temps la synthèse de chalcones et l’obtention de dérivés couplés aux différents vecteurs décrits précédemment (motifs polyaminés,β-CD/CNCx) ; un travail sur la synthèse d’une bis-chalcone via le couplage de Suzuki est également exposé.L’ensemble des molécules obtenues est caractérisé par des analyses RMN 1H, 13C et HRMS. Dans une seconde partie, nous présentons l’ensemble des évaluations biologiques des composés précédemment obtenus. Ces évaluations sont réalisées par un test de viabilité cellulaire (test MTT) sur quatre lignées cancéreuses : deux colorectales (HT-29 et HCT-116) et deux prostatiques (PC-3 et DU-145)Synthesis and vectorization of anticancer agents are major research themes of LCSN. Many natural compoundspossess anti-cancer properties, but they are dropped because of their lack of selectivity to cancer cells or theirlow bioavailability. Thus, great interest is currently focused on the development of drugs specifically vectorizedto cancer cells. The vectors used in this work are polyamine derivatives and nano-objects type β-cyclodextrin /cellulose nanocrystals (β-CD/CNCx). Polyamines allow active targeting of cancer cells through the polyaminetransport system (PTS) overexpressed in these cells. Nano-objects specifically target tumors using a passivetargeting due to the EPR effect. Drugs used in this study are flavonoids, especially chalcones. Indeed,flavonoids, which constitute a large family of natural phenolic compounds, are known for their numerousbiological effects such as antioxidant, anti-inflammatory and anti-proliferative activities. The interest of LCSNfor both chalcones and anticancer agents led us to design new vectorized anti-proliferative compounds. Firstly,this work shows the synthesis of chalcones and their derivatives coupled to various above-described vectors(polyamines units, β-CD/CNCx); a work on the synthesis of a bis-chalcone through the Suzuki coupling reactionis also exposed. All molecules obtained are characterized by 1H NMR, 13C NMR and HRMS analysis. In thesecond part of this work, we present all biological evaluations of compounds previously obtained. Theseassessments are performed through a cell viability test (MTT test) on four cancer cell lines: two colorectal (HT-29 and HCT-116) and two prostate (PC-3 and DU-145) cell lines
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AUBEL, CORINNE. "Effet d'une carence en acide amine sur deux mecanismes majeurs de l'homeostasie des polyamines : le transport membranaire et le catabolisme par la spermidine/spermine n1-acetyltransferase (doctorat)." Clermont-Ferrand 1, 2001. http://www.theses.fr/2001CLF1MM13.
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Schopis, Jia L. "Drug Discovery Studies of the T box Riboswitch: Potential Ligand Inhibition andCofactor Modulation of the tRNA-Antiterminator Complex Recognition." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1461674214.
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Chiteri, Kevin Oyale. "Functional & Phylogenetic Analysis of Arabidopsis thaliana Organic Cation Transporters (OCT5 & OCT1) Genes in Polyamine Transport in Plants." Bowling Green State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1563038129138996.
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Ménard, Florian. "Benzoporphyrines polyaminées et glycolisées : synthèses et tests biologiques." Limoges, 2008. https://aurore.unilim.fr/theses/nxfile/default/8fa60a2e-636b-4c5d-b022-4d474de42c60/blobholder:0/2008LIMO4065.pdf.
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Ce travail porte sur la synthèse multi-étapes, la caractérisation et l'évaluation biologique de nouveaux photosensibilisateurs vectorisés conçus pour une utilisation potentielle en photothérapie dynamique des cancers. Nous avons élaboré plusieurs tétrabenzoporphyrines symétriques substituées par quatre polyamines ou quatre molécules de glucose, dans le but d’augmenter leur sélectivité pour les cellules cancéreuses. Ces dérivés de benzoporphyrines ont été obtenus suivant deux approches distinctes. Ainsi, la fixation des vecteurs (spermidine, spermine, α-D-glucose ou β-D-glucose) a été effectuée soit en fin de synthèse, directement sur le précurseur macrocyclique, soit dans la phase initiale, sur le synthon aldéhydique. Tous les produits finaux obtenus ont révélé leur aptitude à produire de l’oxygène singulet en présence de lumière visible ; finalement, des tests de viabilité cellulaire ont été réalisés, in vitro, sur deux lignées cancéreuses humaines (MCF-7 et HaCaT)This work reports the multi-step synthesis, characterization and biological evaluation of new vectorized photosensitizers designed for their potential use in phototherapy of cancers. This series of molecules consisted in symmetrical tetrabenzoporphyrins to which four glucosyl or polyamine units have been attached in order to increase their selectivity for cancer cells. These benzoporphyrin derivatives were obtained through two distinct approaches: attachment of the vectors (spermidine, spermine, α-D-glucose or β-D-glucose) has been carried out either at the very end of synthesis, on the macrocyclic precursor, or during the initial step, on the aldehydic synthon. All of these final products have proved their ability to produce singlet oxygen in the presence of visible light, and their effects on cell viability have been tested, in vitro, on two human cancer cell lines (MCF-7 and HaCaT)
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Martignoni, Felipe Villa. "TRAXOPRODIL ATENUA AS CONVULSÕES INDUZIDAS POR PENTILENOTETRAZOL." Universidade Federal de Santa Maria, 2010. http://repositorio.ufsm.br/handle/1/8951.
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There is evidence that while polyamines facilitate seizures by positively modulating N-methyl-D-aspartate receptors (NMDAr), selective antagonists of the NR2B-subunit decrease seizures. However, it remains undetermined whether traxoprodil (CP-101,606), an ifenprodil analog that acts as a selective antagonist of the NR2B subunit of the NMDAr, decreases seizure activity. In the current study we investigated whether traxoprodil alters PTZ-induced seizures in adult male Wistar rats by behavioral and electroencephalographical methods. Spermidine (SPD) (2 nmol/site; i.c.v.) facilitated behavioral and electroencephalographical seizures induced by a normally subeffective dose of PTZ (35 mg/kg; i.p.), but did not alter seizure activity induced by convulsant dose of PTZ (70 mg/kg; i.p). Traxoprodil (20 nmol i.c.v.) increased the latency to generalized tonic clonic seizures induced by PTZ (70 mg/kg; i.p). The oral administration of traxoprodil (60 mg/kg) increased the latency to clonic and tonic-clonic seizures, and decreased total time spent in seizures. These data constitute pharmacological evidence supporting a role for NR2B subunit in PTZ-induced seizures. While more studies are necessary to determine whether traxoprodil is a useful anticonvulsant in clinical settings, NR2B subunits may represent new targets of drug development for convulsive disorders.Há evidências de que as poliaminas facilitam convulsões por modular positivamente os receptores N-metil-D-aspartato (NMDAr), e que os antagonistas seletivos a subunidade NR2B do NMDAr têm atividade anticonvulsivante. Entretanto, permanece indeterminado se o traxoprodil (CP-101,606), um análogo do ifenprodil que age como antagonista seletivo na subunidade NR2B do NMDAr, tem efeito anticonvulsivante. Neste estudo investigamos se o traxoprodil altera as convulsões induzidas por pentilenotetrazol (PTZ) em ratos Wistar machos por meio de métodos comportamentais e eletroencéfalográficos (EEG). Espermidina (SPD) (2 nmol/sítio; i.c.v.) facilita as convulsões comportamentais e eletroencéfalográficas induzidas por doses subconvulsivantes de PTZ (35 mg/kg; i.p.), mas não altera a atividade convulsiva induzida por dose plenamente convulsivante de PTZ (70 mg/kg; i.p.). Traxoprodil (20 nmol i.c.v.) aumenta a latência para convulsão tônico-clônica generalizada induzida por PTZ (70 mg/kg; i.p.). A administração oral de traxoprodil (60 mg/kg) aumenta as latências para convulsão clônica e tônico-clônica generalizada e diminui a duração total das convulsões induzidas por PTZ (70 mg/kg; i.p.). Esses dados mostram que o traxoprodil diminui as convulsões induzidas por PTZ, um modelo animal com bom poder de predição de atividade convulsivante em humanos, e sugerem um papel para a subunidade NR2B nas convulsões induzidas por PTZ. Enquanto mais estudos são necessários para determinar se o traxoprodil tem, de fato, atividade anticonvulsivante na clínica, as subunidades NR2B podem representar um novo alvo para o desenvolvimento de drogas anticonvulsivantes.
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Ceretta, Ana Paula Chiapinotto. "Administração sistêmica de espermidina e arcaína altera a memória da tarefa de esquiva inibitória em ratos: envolvimento da dependência de estado." Universidade Federal de Santa Maria, 2006. http://repositorio.ufsm.br/handle/1/11145.
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The polyamines, putrescine, spermidine and spermine, are present in high concentrations in the central nervous system and, because of their policationic nature, they can interact with diverse cellular anionic targets (nucleic acids and proteins) and modulate the learning and memory by interacting with the polyamine binding site at N-methyl-D-aspartate receptor. In this study we investigated the effects of the systemic administration of spermidine and arcaine on the memory of the inhibitory avoidance task in rats. It was also determined whether the effects of the spermidine and arcaine involve state dependence. The animals were trained in an inhibitory avoidance apparatus (0.4 mA, 3s) and tested in the same apparatus 24 hours later. Immediate post-training administration of spermidine (50 mg/kg, i.p.) improved, while arcaine (10 and 30 mg/kg, i.p.) impaired step-down latencies in the inhibitory avoidance test. Administration of spermidine (50 mg/kg, i.p.) 15 minutes before testing did not alter the performance of rats which were injected with spermidine (50 mg/kg, i.p.) or vehicle immediately after training. However, administration of arcaine (30 mg/kg, i.p.) 15 minutes before testing reverted the impairment of memory caused by the administration of arcaine (30 mg/kg, i.p.) immediately after training. Administration of arcaine (30 mg/kg, i.p.) or MK-801 (0.03 mg/kg, i.p.) before testing partially reverted the impairment of memory caused by the administration of arcaine (30 mg/kg, i.p.) or MK-801 (0.03 mg/kg, i.p.) immediately after training, characterizing a crossed state dependence. The results suggest that memory improvement caused by the administration of spermidine immediately after training is not due to state dependence. In contrast, the impairment of memory induced by arcaine is due to state dependence. The crossed state dependence between arcaine and MK-801 supports that state dependence induced by arcaine is related to NMDA receptor hypofunction.As poliaminas, putrescina, espermidina e espermina estão presentes em altas concentrações no sistema nervoso central e, por sua natureza policatiônica, podem interagir com sítios aniônicos de macromoléculas (ácidos nucléicos e proteínas) e modulam o aprendizado e a memória interagindo com o sítio de ligação das poliaminas no receptor N-metil-D-apartato. Neste estudo nós investigamos os efeitos da administração sistêmica de espermidina e arcaína sobre a memória da tarefa de esquiva inibitória em ratos. Também foi determinado se os efeitos da espermidina e arcaína envolvem dependência de estado. Os animais foram treinados em um aparelho de esquiva inibitória (0,4 mA, 3 seg) e testados no mesmo aparelho, 24 horas depois. A administração imediatamente após o treino de espermidina (50 mg/kg, i.p.) melhorou, enquanto que arcaína (10 e 30 mg/kg, i.p.) prejudicou a latência de descida da plataforma no teste da esquiva inibitória. A administração de espermidina (50 mg/kg, i.p.) 15 minutos antes do teste não afetou a performance dos ratos que foram injetados com espermidina (50 mg/kg, i.p.) ou veículo imediatamente após o treino. Entretanto, a administração de arcaína (30 mg/kg, i.p.) 15 minutos antes do teste reverteu o prejuízo da memória causado pela administração de arcaína (30 mg/kg, i.p.) imediatamente após o treino. A administração de arcaína (30 mg/kg, i.p.) ou MK-801 (0,03 mg/kg, i.p.) antes do teste reverteu parcialmente o prejuízo da memória causado pela administração de arcaína (30 mg/kg) ou MK-801 (0,03 mg/kg) imediatamente após o treino, caracterizando dependência de estado cruzada. Estes resultados sugerem que a melhora da memória causada pela administração de espermidina imediatamente após o treino não é devido à dependência de estado. Em contraste, o prejuízo da memória induzido pela arcaína é devido a uma dependência de estado. A dependência de estado cruzada entre arcaína e MK-801. sugere que a dependência de estado induzida pela arcaína envolve a hipofunção do receptor NMDA.
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Tomazi, Lediane. "ARCAÍNA REVERTE A PREFERÊNCIA CONDICIONADA POR LUGAR INDUZIDA POR MORFINA EM CAMUNDONGOS." Universidade Federal de Santa Maria, 2014. http://repositorio.ufsm.br/handle/1/9019.
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Conselho Nacional de Desenvolvimento Científico e TecnológicoThe morphine addiction is a chronic disease that involves biological, cognitive and behavioral changes developed after repeated and compulsive drug use. Even after long periods of abstinence relapses occur to users, especially when faced with situations that resemble the use thereof. The protocol of conditioned place preference (CPP) has been one of the most widely used experimental models to measure the positive reinforcing effects (conditioned place preference) and negative (conditioned place aversion) of several drugs, including morphine. Studies show that antagonists of the N-methyl-D-aspartate (NMDA) block morphine-induced CPP, suggesting that this receptor is involved in the effects of morphine. Since polyamines act at the NMDA receptor, spermidine (SPD) positive allosteric modulating shape and arcaine acting as an antagonist of the polyamine site on this receiver, the purpose of this study the effect of polyamines on the preference induced conditioned place was to evaluate morphine. Adult male Swiss mice were pre-conditioned once a day for 15 minutes for two consecutive device in the CPP, the next day days were subjected twice daily for conditioning sessions with different drugs and protocols for four consecutive days. Twenty-four hours after the last conditioning session the animals were subjected to the test. The CPP score was calculated for the time spent in the compartment paired with the drug on test day, minus the time spent in the same compartment on the second day of the preconditioning. The results of this study showed that morphine (2.5-10 mg/kg, ip) induced CPP, but not aversion induced conditioned place aversion, the SPD (3-30 mg/kg, ip) and arcaine (0.3-3 mg/kg, ip) did not preferably nor induced conditioned place aversion. However, arcaine (3 mg/kg) administered 15 min before morphine (5 mg/kg) attenuated the pre-training acquisition of morphine-induced PCL. The arcaine (3 mg/kg) administered immediately after conditioning with morphine (5 mg/kg) blocked morphine induced PCL. Also, arcaine (3 mg/kg) administered 30 min pretest blocked morphine induced expression CPP. Furthermore, the effect of arcaine on attenuate the effect of morphine was prevented by the administration of SPD before conditioning, but was not reversed by postconditioning pre-test administration and SPD. These data indicate that arcaine blocks the rewarding effect of morphine and arcaine suggests that it could be a therapeutic target in the development of drugs to treat addiction to morphine.
A adicção a morfina consiste em uma doença crônica que envolve alterações biológicas, cognitivas e comportamentais desenvolvida após o uso repetido e compulsivo da droga. Mesmo após longos períodos de abstinência ocorrem recaídas aos usuários, principalmente quando se deparam com situações que lembram o uso da mesma. O protocolo de preferência condicionada por lugar (PCL) tem sido um dos modelos experimentais mais utilizados para mensurar os efeitos reforçadores positivos (preferência condicionada por lugar) e os negativos (aversão condicionada por lugar) de diversas drogas, incluindo a morfina. Estudos mostram que antagonistas do receptor N-Metil-D-Aspartato (NMDA) bloqueiam a PCL induzida por morfina, sugerindo que este receptor está envolvido nos efeitos da morfina. Uma vez que as poliaminas atuam no receptor NMDA, a espermidina (SPD) modulando de forma alostérica positiva e a arcaína agindo como antagonista do sítio das poliaminas neste receptor, o objetivo deste estudo foi avaliar o efeito das poliaminas sobre a preferência condicionada por lugar induzida por morfina. Camundongos Swiss machos foram pré-condicionados uma vez por dia, durante 15 minutos por dois dias consecutivos no aparelho de PCL, no dia seguinte, foram submetidos, duas vezes por dia às sessões de condicionamento, com diferentes drogas e protocolos durante quatro dias consecutivos. Vinte e quatro horas após a última sessão de condicionamento os animais foram submetidos ao teste. O escore de PCL foi calculado pelo tempo gasto no compartimento pareado com a droga no dia do teste, menos o tempo gasto no mesmo compartimento no segundo dia do pré-condicionamento. Os resultados deste estudo mostraram que a morfina (2,5-10 mg/kg, i.p.) induziu PCL, mas não aversão condicionada por lugar, a SPD (3-30 mg/kg, i.p.) e arcaína (0,3-3 mg/kg, i.p.) não induziram preferência e nem aversão condicionada por lugar. No entanto, a arcaína (3 mg/kg) administrada 15 minutos antes da morfina (5 mg/kg) no pré-treino atenuou a aquisição da PCL induzida por morfina. A arcaína (3 mg/kg) administrada imediatamente após o condicionamento com morfina (5 mg/kg) bloqueou PCL induzida por morfina. Ainda, arcaína (3 mg/kg) administrada 30 min pré-teste bloqueou a expressão PCL induzida por morfina. Além disso, o efeito da arcaína em atenuar o efeito da morfina foi prevenido pela administração de SPD antes do condicionamento, mas não foi revertido pela administração pós-condicionamento e pré-teste de SPD. Estes dados indicam que arcaína bloqueia o efeito de recompensa da morfina e sugere que a arcaína poderia ser um alvo terapêutico no desenvolvimento de drogas para tratar a adicção por morfina.
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Gomes, Guilherme Monteiro. "Agentes poliaminérgicos modulam a extinção do medo condicionado contextual em ratos." Universidade Federal de Santa Maria, 2009. http://repositorio.ufsm.br/handle/1/11118.
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Conselho Nacional de Desenvolvimento Científico e TecnológicoPolyamines, such as spermidine and spermine, have been reported to improve memory retention through the activation of N-methyl-D-aspartate receptors (NMDAr). However whether polyamine agonists and antagonists alter extinction remains unclear. In the current study, we investigated whether spermidine and polyamine antagonists that selectively block the NR2B subunit at the NMDAr alter the extinction of contextual conditioned fear in male Wistar rats. While the bilateral intrahippocampal administration of exogenous spermidine (2 nmol/site) facilitated the extinction of fear conditioning, the injection of the antagonists arcaine (0.2 nmol/site), ifenprodil (20 nmol/site) and traxoprodil (0.2 nmol/site), disrupted fear extinction. NMDAr antagonists, at doses that had no effect per se, reversed the facilitatory effect of spermidine on fear extinction. These results suggest that exogenous and endogenous polyamines facilitate the extinction of contextual conditioned fear through activation of NR2B subunit-containing NMDAr in the hippocampus. Since extinction-based exposure therapy is widely used as treatment for a number of anxiety-related disorders, including phobias and post-traumatic stress, the currently reported facilitation of extinction by polyaminergic agents suggest these compounds as putative candidates for drug development.
As poliaminas, como espermidina e espermina, são aminas alifáticas que estão presentes no sistema nervoso central e que se ligam na subunidade NR2B do receptor N-metil-D-aspartato (rNMDA). Tem-se demonstrado que a administração sistêmica, intrahipocampal e intraamígdala de poliaminas melhoram a aquisição e retenção da memória em ratos. Entretanto, seu efeito sobre a extinção do medo condicionado não foi investigado. No presente estudo, investigamos se a administração intrahipocampal de espermidina e de antagonistas seletivos para a subunidade NR2B do rNMDA alteram a extinção do medo condicionado contextual em ratos Wistar machos. A administração intrahipocampal de espermidina (2 nmol/sítio) facilitou a extinção do medo condicionado, enquanto que a injeção dos antagonistas do rNMDA, arcaína (0,2 nmol/sítio), ifenprodil (20 nmol/sítio) e traxoprodil (0,2 nmol/sítio), bloquearam a extinção do medo condicionado contextual. Já a administração dos antagonistas do rNMDA, em doses sem efeito per se, reverteu a facilitação da extinção induzida por espermidina. Estes resultados sugerem que as poliaminas facilitam a extinção do medo condicionado contextual através da ativação da subunidade NR2B do rNMDA hipocampal. Tendo em vista que a terapia baseada em exposição é um método amplamente utilizado como tratamento para diversos tipos de distúrbios relacionados com ansiedade, incluindo fobias e estresse pós-traumático, a facilitação da extinção causada pela administração de espermidina coloca este composto com um possível candidato para o desenvolvimento de novos fármacos para o tratamento destas patologias.
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Zeng, Chunxi. "Riboswitch-targeted Drug Discovery: Investigation of Factors that Affect the T Box Transcription Antitermination Mechanism." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1451943674.
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Ribeiro, Daniela Aymone. "AGENTES POLIAMINÉRGICOS MODULAM A RECONSOLIDAÇÃO DA MEMÓRIA DE MEDO EM RATOS." Universidade Federal de Santa Maria, 2013. http://repositorio.ufsm.br/handle/1/11216.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorThe memory may be studied according with memory's phases, which is acquisition, consolidation and recall. Memories once consolidated, are no more susceptible to interventions, but when reactivated, some of these memories again become labile and vulnerable, and to persist need to have a new stabilization process called reconsolidation. Previous studies described that endogenous polyamines, spermine and spermidine, which bind and modulate the activity of NMDA receptors are involved in memory acquisition and consolidation. However there are no studies showing the effect of these drugs on memory reconsolidation. Accordingly, the aim of this study was investigate the effect of polyamines on fear memory reconsolidation in rats. Male Wistar rats were trained in a fear conditioning apparatus using a 0.4 mA footshock as unconditioned stimulus. Twenty four hours after training, animals were re-exposed to the apparatus in the absence of shock (reactivation session). Immediately after the reactivation session, SPD (1 30 mg/kg, i.p.), the antagonist of the polyamine binding site at the NMDA receptor, arcaine (0.1 10 mg/kg, i.p.) or spermidine plus arcaine were injected, and the animals were tested in the same apparatus 24 h later. Freezing scores at testing were considered a measure of memory. While SPD (3 and 10 mg/kg) improved, arcaine (1 and 10 mg/kg) impaired memory reconsolidation. These drugs had no effect on memory if they were administered in the absence of reactivation, or 6 h after reactivation session. Arcaine (0.1 mg/kg, i.p.) prevented SPD (3 mg/kg)-induced improvement of memory reconsolidation. Accordingly, SPD (1 mg/kg) prevented arcaine (10 mg/kg)-induced impairment of memory reconsolidation. The amnesic effect of arcaine was not reversed by arcaine administration prior to test, ruling out state dependence in this effect. These results suggest that systemic administration of polyamine binding site ligands modulate memory reconsolidation, however further studies are required to elucidate the mechanism by which polyamines modulate memory reconsolidation.
A memória pode ser estudada de acordo com as suas fases, que são a aquisição, a consolidação e a evocação. As memórias, uma vez consolidadas, não podem mais ser modificadas, porém quando reativadas, ou seja, quando recuperadas, muitas destas voltam a se tornar instáveis e vulneráveis e para que persistam precisam passar por um novo processo de estabilização, chamado reconsolidação. Têm sido descrito que as poliaminas endógenas, espermidina e espermina, que se ligam e modulam a atividade do receptor NMDA, estão envolvidas na aquisição e na consolidação da memória. Contudo, não há trabalhos mostrando o efeito destas substâncias na reconsolidação da memória. Desta forma, o objetivo deste estudo foi verificar o efeito das poliaminas na reconsolidação da memória de medo em ratos. Para isso, ratos machos adultos foram treinados na tarefa de medo condicionado contextual, onde receberam três choque de 0,4 mA, com intervalo de 40 seg entre cada choque e, 24 horas após, os animais foram recolocados no aparelho do treino por um período de 3 min, na ausência de choque, para reativar a memória. Após a reativação foi administrado, pela via intraperitoneal, salina, espermidina (1-30 mg/kg), arcaína (0,1-10 mg/kg) ou espermidina mais arcaína e vinte e quatro horas após, os animais foram testados, onde foi avaliado a imobilidade destes durante 6 min. Foram realizados experimentos controles para avaliar a especificidade das drogas no processo de reconsolidação. Além disso, foi avaliado se o possível efeito da arcaína na reconsolidação poderia ser explicado por dependência de estado. Assim, enquanto a espermidina (3 e 10 mg/kg) melhorou, a arcaína (1 e 10 mg/kg) piorou a reconsolidação da memória. Estas drogas não tiveram efeito sobre a memória quando foram administradas na ausência da reativação ou 6 horas após. A arcaína (0,1 mg/kg) preveniu a melhora da reconsolidação da memória induzida pela espermidina (3 mg/kg) e por sua vez, a espermidina (1 mg/kg) preveniu o prejuízo da reconsolidação da memória induzido pela arcaína (10 mg/kg). O efeito amnésico da arcaína não foi revertido pela administração da mesma dose de arcaína antes do teste, descartando a hipótese de dependência de estado para o efeito da arcaína na reconsolidação. Estes resultados sugerem que a administração sistêmica dos ligantes do sítio de ligação das poliaminas do receptor NMDA modulam a reconsolidação da memória, todavia são necessários mais estudos a fim de elucidar o mecanismo pelo qual as poliaminas modulam a reconsolidação da memória.
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Plym, Forshell Tacha Zi. "Examining the role of metabolism in Myc-driven tumorigenesis." Doctoral thesis, Umeå universitet, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-46564.
Full textAbstract:
Myc transcriptionally regulates genes involved in processes such as cell proliferation, metabolism, differentiation, and angiogenesis. MYC expression is deregulated in many types of human cancer; therefore discovering the mechanisms behind MYCs role in tumorigenesis is essential. In this dissertation, I have focused on several Myc target genes, Spermidine synthase (Srm); Lactate dehydrogenase (Ldh); 3-phosphoglycerate dehydrogenase (Phgdh); Serine hydroxymethyltransferase (SHMT) 1 and 2; and Pim-3 (a member of the Pim family of serine/threonine kinases). These enzymes play a role in various functions: Spermidine synthase (polyamine synthesis); Lactate dehydrogenase (glycolysis); Phgdh and Shmt (serine metabolism); and Pim-3 (cell signaling). In order to elucidate the impact Myc over-expression has on metabolism in tumorigenesis, we use human cell lines, and transgenic mice as well as cell lines and tissues derived from these mice. The impact of inhibition of these target genes on Myc-driven tumorigenesis was done by genetically inhibiting the target gene (using RNAi or mouse models) or inhibiting the protein with a chemical inhibitor. Investigating these Myc target genes will help determine if inhibition of Myc target genes is a viable approach for chemotherapeutics, and under what conditions this inhibition may be the most valuable. In paper I, we examine SRM; a highly expressed enzyme in the polyamine synthesis pathway that converts putrescine to spermidine, and is important for actively growing cells. Genetic inhibition via RNAi against Srm, or chemical inhibition of Srm, resulted in decreased proliferation of B-cell tumor lines from transgenic mice in vitro. In vivo treatment of λ-Myc transgenic mice with a chemical SRM inhibitor exhibited a significant chemopreventative effect on tumor formation. These results support previous findings that inhibition of polyamine synthesis pathway enzymes has a place in cancer therapy. Many Myc target genes have been suggested as attractive targets in battling Myc-driven tumorigenesis. Surprisingly in paper II, when we analyzed the inhibition of other Myc target genes, such as Ldh, Shmt, and Phgdh, we found that inhibition of these genes did not inhibit Myc-driven tumorigenesis to any significant degree. However, inhibition of Ldh, Phgdh and Shmt2 had a notable effect on in vitro Ras-driven transformation. These findings suggest that chemotherapeutic inhibition of metabolic genes such as Ldh, Phgdh and Shmt2 may be effective in genetically defined settings, keeping in mind the oncogenic lesion behind the tumor. The Pim kinase family consists of three serine/threonine kinases, Pim1-3. In paper III, we found that Pim-3 is a direct Myc target gene and that Pim-3 expression is high in Burkitt Lymphoma samples taken from human patients, as well as spontaneously arising lymphomas from Myc transgenic mice. We also found that inhibition of Pim-3 using a pan-Pim kinase inhibitor, Pimi, in these spontaneously arising Myc lymphomas resulted in caspase independent cell death. These results indicate that Pim kinase inhibition may be a potential chemotherapeutic strategy in human lymphomas that rely on Pim-3 kinase expression.
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Carvalho, Fabiano Barbosa. "ESPERMIDINA DIMINUI A ATIVIDADE DA ENZIMA Na+,K+-ATPase PELA VIA DE SINALIZAÇÃO NMDA/NOS/GMPc/PKG EM HIPOCAMPO DE RATOS." Universidade Federal de Santa Maria, 2011. http://repositorio.ufsm.br/handle/1/11184.
Full textAbstract:
Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorSpermidine (SPD) is an endogenous polyamine with polycationic structure present in the central nervous system of mammals. SPD regulates biological processes, such as Ca2+ influx by glutamatergic N-methyl-D-aspartate receptor (NMDA receptor), which has been associated with nitric oxide synthase (NOS) and cGMP/PKG pathway activation and a decrease of Na+,K+-ATPase activity in rats cerebral córtex synaptossomes. Decreased Na+,K+-ATPase activity, as well as decreased enzyme expression, directly impairs neurotransmitter signaling with deleterious consequences on learning and memory. The enzyme Na+,K+-ATPase establishes Na+ and K+ gradients across membranes of excitable cells and by this means maintains membrane potential and controls intracellular pH and volume. However, it has not been defined whether SPD modulates Na+,K+-ATPase activity in the hippocampus. In this study we investigated whether SPD alters Na+,K+-ATPase activity in slices of hippocampus from rats, and possible underlying mechanisms. Hippocampal slices and homogenates were incubated with SPD (0.05-10 μM) for 30 minutes. SPD (0.5 and 1 μM) decreased Na+,K+-ATPase activity in slices, but not in homogenates. MK-801 (100 μM), a non-competitive antagonist of NMDA receptor, arcaine (0.5 μM), an antagonist of the polyamine binding site at the NMDA receptor, and L-NAME (100 μM), a nitric oxide synthase inhibitor, prevented the inhibitory effect of SPD (0.5 μM). ODQ (10 μM), a guanylate cyclase inhibitor, and KT5823 (2 μM), a protein kinase G inhibitor, also prevented the inhibitory effect of SPD on Na+,K+-ATPase activity. SPD (0.5 and 1.0 μM) increased NO2 plus NO3 (NOx) levels in slices, MK-801 (100 μM) and arcaine (0.5 μM) prevented the effect of SPD (0.5 μM) on the NOx content. These results suggest that SPD-induced decrease of Na+,K+-ATPase activity involves NMDA/NOS/cGMP/PKG pathway.
A espermidina (SPD) é uma poliamina endógena com estrutura policatiônica presente no sistema nervoso central (SNC) de mamíferos. A SPD regula muitos processos biológicos, como o influxo de cálcio através dos receptores glutamatérgicos N-metil-D-aspartato (NMDA), o qual tem sido associado com a ativação da enzima óxido nítrico sintase (NOS) e da via de sinalização da guanosina mono fosfato cíclica/proteína quinase dependente de GMPc (GMPc/PKG). Sabe-se que uma diminuição da atividade da Na+,K+-ATPase, bem como a sua expressão, prejudica diretamente a sinalização de neurotransmissores, comprometendo tanto aprendizado e a memória. A enzima Na+,K+-ATPase estabelece os gradientes de Na+ e K+ através da membrana de células excitáveis e desta forma mantém o potencial de membrana e contribui para o controle do volume e do pH celular. No entanto, não está bem definido se a SPD modula a atividade da Na+,K+-ATPase no hipocampo de ratos. Neste estudo foi investigado se SPD altera a atividade da Na+,K+-ATPase em fatias de hipocampo de ratos, e o possível mecanismo envolvido neste processo. As fatias e o homogeneizado de hipocampo foram incubados com SPD (0,05-10 M) por 30 minutos. SPD (0,5 e 1 M) diminuíram a atividade da Na+,K+-ATPase em fatias, mas não no homogeneizado de hipocampo. MK-801 (100 μM), um antagonista não competitivo do receptor NMDA, arcaína (0,5 M), um antagonista do sítio de ligação das poliaminas no receptor NMDA, e L-NAME (100 μM), um inibidor da NOS, preveniram o efeito inibitório da SPD (0,5 M). ODQ (10 μM), um inibidor da enzima guanilato ciclase, e KT5823 (2 μM), um inibidor da proteína quinase dependente de GMPc, também preveniram o efeito inibitório da SPD sobre a atividade da Na+,K+-ATPase. SPD (0,5 e 1,0 μM) aumentaram os níveis de NO2 plus NO3 (NOx) nas fatias de hipocampo. MK-801 (100 μM) e arcaína (0,5 μM) preveniram o efeito da SPD (0,5 μM) sobre conteúdo de NOx. Estes resultados sugerem que a diminuição da atividade da Na+,K+-ATPase induzida pela SPD envolve a via de sinalização NMDA/NOS/GMPc/PKG.